DIVISION OF NONHUMAN PRIMATE SYSTEMS BIOLOGY PROJECT SUMMARY The Division of Nonhuman Primate Systems Biology provides an investigative and resource infrastructure to create and use genomic, proteomic, and computational methods to improve the translational impact of nonhuman primate biomedical models. The Division conducts research and resource development activities in the broad area of nonhuman primate systems biology and includes two service cores, the High-throughput Molecular Profiling Core and the Statistical Analysis and Computational Modeling Core. Global molecular profiling and computational resources can be accessed by external investigators through collaboration with Division scientists or directly through the Cores using a fee-for-service mechanism. Specific Aims associated with the research and resource development activities of the Division include: 1) Develop advanced methods for microbiome and single-cell transcriptome analysis for use with nonhuman primate models. The interplay between the microbiome and host health and disease is an exciting and burgeoning area of research. The development of these methods will better define this interrelationship with the goal of future manipulation to enhance therapeutic strategies or to improve vaccine efficacy. Additionally, in collaboration with Dr. Alex Shalek (Massachusetts Institute of Technology), single-cell transcriptome analysis and RNA profiling will be performed on individual cells from specific immune cell-types isolated from nonhuman primates under different conditions. Insights will be gained as to how and why individual cells respond differently to the same condition and how these responses change between conditions. This high resolution view of transitions between states will ultimately lead to a better understanding of both intra- and intercellular regulatory circuits and the dynamic responses of multicellular populations. 2) Develop molecular profiling and computational approaches for quantifying transcript expression from complex immune loci such as the rhesus macaque major histocompatibility (MHC) loci or FC-? receptor genes. These genes serve critical roles in host immune responses and are associated with many human diseases including HIV infection and AIDS. Therefore it is paramount to establish proven methods for determining differences in transcript levels between healthy and disease states. 3) Develop genome editing methods and resources for use in mechanism of action studies and for drug target validation. Systems-level analyses provide detailed information on host responses, which in turn can be used to identify mechanistic hypotheses or therapeutic targets. Similarly, genetic variations and polymorphisms can impact host susceptibility to infection or disease progression. Here, we will develop a combination of cell culture, genome editing, and computational approaches to engineer specific genetic variations into macaque CD4+ T cells and evaluate their effect on phenotypic outcomes. These results will identify potential gene targets in rhesus macaques for 1) drug treatment validation and 2) for genome modification with the long term goal of developing engineered models of human disease.